S-adenosylhomocysteine, known as AdoHcy, is an intermediate in the metabolism of the sulfur-containing amino acids methionine and cysteine. AdoHcy is formed by the donation of a methyl group from S-adenosylmethionine (SAM) to biomolecules undergoing methylation reactions. AdoHcy is then metabolized by the enzyme S-adenosylhomocysteine hydrolase, known as AHCY or SAHH or SAH hydrolase, which reversibly hydrolyses AdoHcy to adenosine and homocysteine. Homocysteine can be remethylated back to methionine or undergo a series of metabolic steps leading to the biosynthesis of glutathione or cysteine. Following the hydrolysis of AdoHcy, homocysteine can also be secreted from the body or converted into the anti-oxidant, glutathione, by a series of transulfuration pathway reactions. Glutathione is a major anti-oxidant in the body. The relative ratio between oxidized and reduced forms of glutathione is thought to be an important indicator of oxidative state.
Furthermore, the ratio between SAM and AdoHcy is critical for many biological processes, as AdoHCY can inhibit many methyltransferases that use SAM as a methyl donor. Thus, the rate of conversion of AdoHcy to Hcy is a critical regulator of many biological reactions involving phospholipids, proteins, and nucleic acids. Various nucleosides and nucleoside derivatives act as inhibitors of AHCY. Chiang, Pharmacol Ther 1998, 77, 2, 115-134.
Homocysteine metabolism is also dependent on the nutrients folate, vitamin B12 and vitamin B6. Obeid et al, FEBS Letters 2006, 580:2994-3005. These nutrients are cofactors for the enzymes that remethylate Hcy back to methionine (folate, B12) or convert it to glutathione (B6).
AHCY is a 432 amino acid protein, which is a thioether hydrolase. AHCY is a cytosolic enzyme that has been found in a wide variety of cells. Walker, et al. Can. J. Biochem. 1975 53: 312-319. The sequence of AHCY is disclosed in International Patent Application Publication No. WO 2005/015221.
AHCY catalyzes the conversion of S-adenosyl-homocysteine to homocysteine and adenosine. Because of the key role of AdoHcy in the synthesis of cysteine, and the role of S-adenosylmethionine as a universal methyl donor, misregulation of AHCY can affect methylation of phosphlipids, proteins, DNA and RNA.
Epidemiological evidence demonstrates that increased levels of homocysteine are associated with many diseases, including cardiovascular disease, stroke, and neurodegenerative diseases such as Alzheimer's Disease. Hyperhomocysteinemia, which may be caused by folic acid deficiency, can contribute to Alzheimer's Disease. Morris, Lancet Neurol. 2003 2(7):425-8. Further, the known AHCY inhibitor 3-deaza-adenosine (DZA) has been shown to prevent oxidative damage and cognitive impairment in mice. Shea et al, Neuromolecular Medicine 2004, 5:173-182. In clinical studies, folate deficiency was associated with neurological disorders such as Alzheimer's disease. Ho et al., Neurobiology of Disease, 2003 14: 1, 32-42.
Seshadri et al, N Engl. J Med, 2002, 346:476-483, in a study of data from the Framingham Heart Study, found that increased homocysteine levels in plasma was an independent risk factor for dementia and Alzheimer's Disease. See also Morris, Lancet Neurology 2003, 2:425-428.
Hyperhomocysteinemia is a known risk factor for arterial vascular disease and venous thrombosis. Gellekink et al, Eur J Hum Genet. 2004 12(11):942-8; cardiovascular disease, Levine et al, Prog Neuropsych Biol Psych 2005, 29(7):1181-91; schizophrenia, Haidemenos et al, Prog Neuropsychopharmacol Biol Psychiatry. 2007 15; 31(6):1289-96; and bipolar disorder, Levine et al. Elevated homoscysteine levels have also been shown to be risk factors for stroke and Parkinson's Disease. Herrmann et al, Fortschr Neurol Psychiatr. 2007 75(9):515-27. Further, animal studies suggest that increased homocycsteine levels may be a factor in osteoporosis. Herrmann et al, Clin. Chem. 2007, 53(8):1455-61.
One possible method for treating diseases via the AHCY pathway is to develop mechanisms for clearing homocysteine from the body. For example, compounds or substances that increase the rate of vitamin B clearance of homocysteine in vivo may find utility as agents for treating disease associated with high levels of homocysteine. A second method of interfering with the AHCY pathway is to decrease production of homocytseine, i.e. to develop compounds that can inhibit production of homocysteine in vivo. For example, compounds or substances which inhibit AHCY may decrease the extent of hydrolysis of S-adenosyl homocysteine into homocysteine and adenosine.
The inventors have identified a novel group of compounds which act as inhibitors of S-adenosyl homocysteine hydrolase, thereby inhibiting the hydrolysis of S-adenosyl homocysteine into homocysteine and adenosine.